Red blood cell (RBC) utilization is decreasing markedly in the United States, Canada, and the United Kingdom as a result of blood conservation programs. To date, the safety of these strategies is supported by randomized clinical trials (RCTs) of liberal and restrictive transfusion strategies in specific patient populations and by our own observational mortality data from a large community hospital setting. However, more recent RCTs have highlighted that the potential risks and benefits of restrictive transfusion strategies may differ according to the patient population studied. Decreased hospital acquired infections, increased myocardial injury, and an effect on mortality have been identified in specific transfusion RCTs. Validating these findings in general clinical practice and identifying which patient subgroups are at highest risk of adverse events will inform national transfusion guidelines and help promote best practices. In parallel, recent biological and epidemiological studies have highlighted the potential impact on recipient outcomes of blood donor factors such as age and gender. Preliminary findings from our linked donor, component, and transfusion recipient analysis show donor age and sex effects on recipient mortality, and support a larger, well controlled analysis of donor factors. The Kaiser Permanente Northern California (KPNC) hospital system transfusion cohort will include granular data from electronic medical records of more than 100,000 transfused patients at 21 hospitals from 2010-2016 as well as linked donor demographic data from Blood Systems Research Institute. Using innovative statistical techniques to control for confounding and indication bias, we propose to examine the following Specific Aims: 1) Controlling for patient factors and hemoglobin levels, we will determine how blood conservation has impacted the incidence of 3 adverse outcomes (hospital acquired infection, myocardial injury, and mortality) among transfused hospitalized patients. We hypothesize that restrictive red blood cell transfusion strategies will not impact mortality but will be associated with decreased incidence of infection and increased rates of myocardial injury in specific populations. 2) Controlling for recipient characteristics, blood processing methods, and storage duration, we will determine whether donor factors (age and sex) are associated with adverse clinical outcomes in transfused hospitalized patients. We hypothesize that blood from younger and male donors will be associated with decreased organ failure, incidence of infection, hospital length of stay, and mortality in transfused hospitalized patients. Results from this project utilizing comparative effectiveness methods may impact clinical care in tailoring RBC transfusion guidelines for specific patient conditions and can inform planning for future randomized clinical trials. In addition, they may generate hypotheses for basic science research of donor factors that impact the safety and efficacy of RBC transfusion.